Olopatadine is the international non-proprietary name of {(11Z)-11-[3-(dimethylamino)propylidene]-6,11-dihydrodibenzo[b,e]oxepin-2-yl}acetic acid, having the following formula (I)
and is usually employed as an antihistaminic and is, at present, commercialized to treat eye disorders associated with allergies and allergic conjunctivitis or to treat hives and dermatitis as well.
Several syntheses of olopatadine are known. Such syntheses often comprise a Wittig reaction on the substrate called isoxepac of formula (II)
upon protection with a protecting group forming an ester, and the subsequent cleavage of said protecting group to give the desired compound.
WO2010/007056 discloses the preparation of olopatadine by means of a Wittig reaction carried out on the isoxepac protected by means of esterification with alkyls, cycloalkyls, aryls, aralalkyls or heterocycles or protected in amidic form.
WO2010/121877 discloses the preparation of olopatadine by means of a Wittig reaction carried out on the isoxepac protected by means of esterification with a C1-C4 alkyl.
Such syntheses necessarily require the isolation of the intermediate, i.e. of the protected isoxepac, before carrying out the Wittig reaction and often the isolation of the protected olopatadine as well, before the step of cleaving the protecting group. Such isolations involve laborious recovery operations, the possible purification and drying of said intermediate compounds.
It can be easily understood that, in the framework of the industrial chemical synthesis, each reaction step involving the isolation of an intermediate product has a significant impact on production costs; therefore there is a continuous research on synthesis processes that could be industrially implemented by means of the lowest possible number of reaction steps and without the isolation of the intermediates.